Exploring host GSK3β-53BP1 axis in immune control of solid tumor progression

Summary Head and neck squamous cell carcinoma (HNSCC) is a major global health challenge, with a high rate of recurrence and metastasis leading to a median survival of only 10-12 months for patients with advanced disease. While immune checkpoint blockade (ICB) has revolutionized treatment, its effectiveness remains limited, with a response rate of only 11-18% at six months. This proposal seeks to address the critical issue of T cell exhaustion (TEX), which hampers the efficacy of immunotherapies like ICB and adoptive cell transfer (ACT). Our preliminary data indicate that TEX is associated with the accumulation of DNA double-strand breaks (DSBs), resulted from the inhibition of the 53BP1-dependent DNA repair activity by glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation. We have developed a knock-in mouse model that expresses a mutant 53BP1 which prevents GSK3β-mediated phosphorylation and inhibition. Using our model, we discovered that blocking this GSK3β- 53BP1 interaction in mouse models significantly enhanced T cell survival following ironing radiation-induced DSBs, infiltration into tumors, and immunotherapy responses in pre-clinical models HNSCC. We hypothesize that inhibition of the GSK3B-53BP1 axis in T cells will enhance DNA repair, promote survival from DNA damage, limit TEX, and increase immune effector function in HNSCC. Aim 1 focuses on understanding how GSK3β inhibits 53BP1 in DNA repair and T cell survival following radiation, hypothesizing that this interaction is crucial for controlling TEX. Aim 2 will investigate the effects of disrupting the GSK3β-53BP1 axis on tumor-infiltrating lymphocyte (TIL) function and the response to ICB alone, or in combination with radiation. Aim 3 tests the therapeutic potential of using 53BP1 mutant T cells in ACT for HNSCC. This study will be the first to explore the GSK3β-53BP1 axis in cancer immunity, aiming to enhance DNA repair, reduce TEX, and improve the efficacy of immunotherapies for HNSCC and other solid tumors. Project Number: 1R01CA299654-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Fen Xia (+1 co-PI) | Institution: UNIV OF ARKANSAS FOR MED SCIS, LITTLE ROCK, AR | Award Amount: $628,980 | Activity Code: R01 | Study Section: Radiation Therapeutics and Biology Study Section[RTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293712